1. Field of the Invention
This disclosure relates to compounds, compositions and methods for the treatment of various disorders. In particular, the disclosure relates to compounds which antagonize the activity of the protein Smoothened and thereby inhibit the Hedgehog signaling pathway.
2. Description of Related Art
The Hedgehog (Hh) signaling pathway is an important regulator of cellular processes. Hedgehog protein family members mediate events in both vertebrates and invertebrates critical to developmental patterning processes, cellular differentiation, and proliferation. Three vertebrate Hedgehog genes, Sonic Hedgehog (Shh), India Hedgehog (Ihh) and Desert Hedgehog (Dhh), are known. The translated gene products are secreted proteins which are post-translationally modified via autoproteolytic cleavage, palmitoylation, and cholesterol attachment. Post-translational modification acts in part to control Hh proteins spatial and temporal distributions, allowing the proteins to function as morphogens. The inductive actions of Hh proteins occur in both embryos and adult cells, acting to modulate morphogenetic patterns and causing differentiation.
The Hedgehog signaling pathway involves the three Hh ligands (Dhh, Shh or Ihh), the twelve transmembrane protein Patched (PTCH1), the seven transmembrane protein Smoothened (SMO), and the Gli family of transcription factors as well as other regulatory proteins. The Hh signaling pathway normally resides in an inactive state in the absence of Hh ligand, due to Patched protein interacting with Smoothened and thereby inhibiting the activity of Smoothened. Binding of Hh ligands to Patched disrupts the interaction of Patched with Smoothened thereby causing its activation and migration to the plasma membrane. In mammalian systems, Smoothened and other downstream pathway components are localized to non-motile cilia as part of the signaling activation process. Smoothened activation in turn leads to a series of events that result in Gli transcription factors (particularly Gli1 and Gli2) translocating into the nucleus whereby they activate transcription of their target genes. Target genes of the Gli transcription factors include Wnts, TGFβ, c-Myc, cyclins, as well as Patched and Gli themselves.
Under normal conditions, the Hh signaling pathway is tightly controlled given the importance of proper cell proliferation, cell differentiation, and embryonic pattern formation. However, under aberrant conditions, deregulation of the Hedgehog pathway may occur and lead to disease. For example, individuals with Gorlin's disease, a hereditary syndrome which carries a high risk of brain and skin cancer, are observed to have loss of function mutations in Patched. Gain of function mutations in Smoothened or Gli proteins are linked to glioblastoma and basal cell carcinoma (the most common form of skin cancer in the United States). Inappropriate activation of Hh signaling is implicated in the metastasis of prostate cancer. In human pancreatic tumors, abnormal expression of Patched, Smoothened, and sonic Hedgehog also has been observed. Importantly, even when components of the Hh signaling pathway are not directly mutated in a cancer, pathway activation can still be central to the cancer proliferation; the tumor cells establish an active autocrine loop through in which they both make and respond to Hh ligand thereby facilitating proliferation.
Further supporting the role of aberrant Hh pathway signaling in cancer are the effects of cyclopamine in xenograft mouse models of cancer. Cyclopamine is a naturally occurring alkaloid which was discovered to be a Hedgehog pathway antagonist. In a range of xenograft models of different cancer types, treatment with cyclopamine has been found to slow progression of tumor growth or suppress metastasis.
Thus, inappropriate Hedgehog signaling may cause or contribute to a range of diseases including a broad range of cancers. The role of Hh signaling in the disease may be due to loss or gain of function mutations of members of the pathway or inappropriate activation of the pathway. Moreover, small molecule antagonists can suppress or reverse the effects of inappropriate Hedgehog signaling. Accordingly, molecules which antagonize the Hedgehog signaling pathway, such as modulators of Smoothened activity, are needed and are therapeutically useful.